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Pseudohypoparathyroidism: A case of hypocalcemia and hypothyroidism diagnosed during the postpartum period

Lim KP, Yong SL

Malays Fam Physician, 2019;14(1):31-34.
PMID: 31289630

We describe a 29-year-old Para 1 post-Emergency Lower Segment Caesarean Section (EMLSCS) for fetal distress and Preterm Rupture of the Membrane (PROM) referred by the Obstetric team for persistent bradycardia. She had the typical features of Albright's Hereditary Osteodystrophy (AHO). The laboratory investigation revealed hypocalcemia, hyperphosphatemia with a high Parathyroid hormone (PTH) level and low free Thyroxine 4 (fT4) with high Thyroid Stimulating Hormone (TSH). The patient was diagnosed with Pseudohypoparathyroidism (PHP) Type 1A associated with TSH resistance based on the somatic features of AHO present as well as biochemical and radiological abnormalities.
Fulltext Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

Lim KP, Zainal NS

Front Mol Biosci, 2021;8:623475.
PMID: 33937323 DOI: 10.3389/fmolb.2021.623475

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.
Expression and purification of a recombinant scFv towards the exotoxin of the pathogen, Burkholderia pseudomallei

Lim KP, Li H, Nathan S

J Microbiol, 2004 Jun;42(2):126-32.
PMID: 15357306

A single chain variable fragment (scFv) specific towards B. pseudomallei exotoxin had previously been generated from an existing hybridoma cell line (6E6AF83B) and cloned into the phage display vector pComb3H. In this study, the scFv was subcloned into the pComb3X vector to facilitate the detection and purification of expressed antibodies. Detection was facilitated by the presence of a hemagglutinin (HA) tag, and purification was facilitated by the presence of a histidine tag. The culture was grown at 30 degrees C until log phase was achieved and then induced with 1 mM IPTG in the absence of any additional carbon source. Induction was continued at 30 degrees C for five h. The scFv was discerned by dual processes-direct enzyme-linked immunosorbent assays (ELISA), and Western blotting. When compared to E. coli strains ER2537 and HB2151, scFv expression was observed to be highest in the E. coli strain Top10F'. The expressed scFv protein was purified via nickel-mediated affinity chromatography and results indicated that two proteins a 52 kDa protein, and a 30 kDa protein were co-purified. These antibodies, when blotted against immobilized exotoxin, exhibited significant specificity towards the exotoxin, compared to other B. pseudomallei antigens. Thus, these antibodies should serve as suitable reagents for future affinity purification of the exotoxin.
Utilisation of community pharmacists by the general public in Malaysia

Chua SS, Lim KP, Lee HG

Int J Pharm Pract, 2013 Feb;21(1):66-9.
PMID: 23301536 DOI: 10.1111/j.2042-7174.2012.00219.x

The study was conducted to assess how the general public in the Klang Valley, Malaysia, utilised community pharmacists.
Bacterial expression of the scFv fragment of a recombinant antibody specific for Burkholderia pseudomallei exotoxin

Su YC, Lim KP, Nathan S

J. Biochem. Mol. Biol., 2003 Sep 30;36(5):493-8.
PMID: 14536033

The scFv antibody towards the Burkholderia pseudomallei exotoxin was previously constructed by phage display and exhibited good specificity towards the exotoxin. We report here the optimization of the scFv expression in an E. coli expression system. Four different E. coli strains (ER2537, TG1, HB2151, and XL1-Blue) were examined for optimal expression of the scFv protein. Two types of carbon source (i.e. 0.2% glucose and 0.2% glycerol) were also tested for their ability to induce the scFv expression. Cells that carried the scFv construct were grown at 30 degrees C and induced with 0.05 mM IPTG. The expression was then monitored by SDS-PAGE, Western blotting, and indirect ELISA. The Western blot profile showed different levels of the scFv expression among the host strains; XL1-Blue exhibited the highest level of the scFv protein expression. Glycerol at a concentration of 0.2% (v/v) significantly increased the scFv protein expression level when compared to 0.2% (w/v) glucose. Further optimization demonstrated that the scFv protein expression in XL1-Blue was the most optimal with a glycerol concentration as low as 0.05%. However, by indirect ELISA, only the scFv protein that was expressed in 0.2% (v/v) glycerol exhibited high specificity towards the Burkholderia pseudomallei exotoxin.
Fulltext The origins, roles and therapies of cancer associated fibroblast in liver cancer

Zulaziz N, Chai SJ, Lim KP

Front Oncol, 2023;13:1151373.
PMID: 37035187 DOI: 10.3389/fonc.2023.1151373

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is often preceded by chronic inflammation such as liver fibrosis and cirrhosis. Different cell types are believed to give rise to liver-specific cancer associated fibroblast (CAF), these include resident fibroblast, hepatic stellate cell, liver cancer cell, hepatic sinusoidal endothelial cell and mesenchymal stromal cell. The abundance of fibroblasts has contributed to the cancer progression, immune modulation and treatment resistance in HCC. In this review, we discussed the origins, subtypes and roles of cancer associated fibroblasts in HCC. Their specific roles in shaping the tumor microenvironment, facilitating cancer growth, and modulating different immune cell types to confer a permissive environment for cancer growth. CAF is now an attractive therapeutic target for cancer treatment, however specific therapeutic development in HCC is still lacking. Hence, we have included preclinical and clinical development of CAF-specific interventions for other cancer types in this review. However, most CAF-specific therapies have resulted in disappointing clinical outcomes, likely due to the difficulties in differentiating CAF from normal fibroblast. A thorough understanding of the characteristics and functionalities of CAF is warranted to further improve the therapeutic efficacy of anti-CAF therapies.
Fulltext Parathyroid Carcinoma: Analysis of Patient Characteristics and Outcomes in a Retrospective Review of Eight Cases seen in a Single Center

Shahar S, Lim KP, Mohamad M

J ASEAN Fed Endocr Soc, 2019;34(2):229-232.
PMID: 33442162 DOI: 10.15605/jafes.034.02.17

Eight cases of parathyroid carcinoma were identified (8 females; median age 45 years, range 28-72). Half of whom were diagnosed preoperatively. Hypercalcemic symptoms were seen in 87.5% of the patients and the main complication was nephrolithiasis. At presentation, the median calcium was 3.675 mmol/L, median phosphate of 0.68 mmol/L, median intact parathyroid hormone (iPTH) was 211 pmol/L. Five patients had regional nodes metastasis and 1 had distant metastasis to the lungs. Parathyroid gland invasion to adjacent structures was seen in 62.5% of cases while another 62.5% showed capsular or vascular infiltration on histology with median tumour size of 3.2 cm. Recurrent hypercalcemia occurred in 50% of the patients with median time of recurrence of 21 months. In this case series, we found that patients with severe hypercalcemia and high iPTH also exhibited a high index suspicion of PC.
Fulltext Metastatic Bone Disease Secondary to Bronchial Adenocarcinoma in a Patient with Paget's Disease of the Bone

Lim KP, Kok WH, Kamaruddin NA

J ASEAN Fed Endocr Soc, 2018;33(1):63-68.
PMID: 33442113 DOI: 10.15605/jafes.033.01.11

A 69-year-old female complained of intermittent left hip pain for the past 3 years. Biochemical tests revealed normal serum calcium and phosphorus with markedly raised alkaline phosphatase. MRI of the hip revealed extensive marrow signal abnormalities at the left pelvic bone, while CT of the thorax revealed a spiculated lung nodule at the left lower lung lobe. In order to diagnose either primary, metastatic bone tumour or Paget's disease of the bone (PDB), an open biopsy of the left iliac bone was performed. The histopathology of bone biopsy of the left iliac bone was consistent with PDB. A CT guided biopsy of the lung mass done later revealed adenocarcinoma of the lung. She had 18F-FDG PETCECT Scan for staging evaluation and result was suggestive of new bony metastases. Patient was started on IV Zoledronic acid for treatment of the PDB. In view of the stage 4 lung adenocarcinoma with bony metastases, patient was scheduled for palliative chemotherapy.
Fulltext The Effect of Individualised Glycemic Intervention on Wound Healing Rate in Diabetic Foot Ulcer (The EIGIFU Study)

Lim KP, Nasruddi AB, Rani NM

J ASEAN Fed Endocr Soc, 2018;33(1):22-27.
PMID: 33442107 DOI: 10.15605/jafes.033.01.04

Objective: To evaluate the association of glycated haemoglobin (HbA1c) reduction and wound healing in patients with diabetic foot ulcer (DFU).
Methodology: A 12-week prospective, non-controlled, interventional study in suboptimal-controlled T2DM patients with DFU was conducted. Antidiabetic medications were adjusted with the aim of at least 1% in relation to patient's individualised HbA1c target. The wound area was determined by using specific wound tracing. The daily wound area healing rate in cm2 per day was calculated as the difference between wound area at first visit and the subsequent visit divided by the number of days between the two visits.
Results: 19 patients were included in the study. There was a significant HbA1c reduction from 10.33 %+1.83% to 6.89%+1.4% (p<0.001) with no severe hypoglycaemia. The median daily wound area healing rate was 0.234 (0.025,0.453) cm2/day. There was a strong positive correlation between these two variables (r=0.752, p=0.01). After dividing the patients into four quartiles based on final HbA1c and comparing the first quartile vs fourth quartile, there was a significant difference in daily wound area healing rates (0.597 vs 0.044 cm2/day, p=0.012).
Conclusion: There was a positive correlation between HbA1c reduction and wound healing rate in patients with DFU. Although this is an association study, the study postulated the benefits of achieving lower HbA1c on wound healing rate in DFU which require evidence from future randomised controlled studies.
The influence of sex, race and dialect on peptic ulcer and non-ulcer dyspepsia in Singapore

Kang JY, Guan R, LaBrooy SJ, Lim KP, Yap I

Ann Acad Med Singap, 1983 Oct;12(4):527-31.
PMID: 6611105

A consecutive series of 2,277 patients presenting for upper gastrointestinal endoscopy was analysed. The following groups of patients were studied with reference to sex, race and dialect groups: those presenting with dyspepsia but no haemorrhage, those presenting with upper gastrointestinal haemorrhage, those with non-ulcer dyspepsia, gastric ulcer and duodenal ulcer. Males out-numbered females in all diagnostic groups. Male and female Malays were under-represented in all diagnostic groups when compared to the Singapore population. Amongst female Chinese, there was an excess of Cantonese patients and an under-representation of Teochew patients in most diagnostic groups. These dialect differences were not remarkable amongst male Chinese. The possible reasons for these differences and their significance are discussed.
Translational genomics and recent advances in oral squamous cell carcinoma

Chai AWY, Lim KP, Cheong SC

Semin Cancer Biol, 2020 04;61:71-83.
PMID: 31542510 DOI: 10.1016/j.semcancer.2019.09.011

Oral squamous cell carcinomas (OSCC) are a heterogeneous group of cancers arising from the mucosal lining of the oral cavity. A majority of these cancers are associated with lifestyle risk habits including smoking, excessive alcohol consumption and betel quid chewing. Cetuximab, targeting the epidermal growth factor receptor was approved for the treatment of OSCC in 2006, and remains the only molecular targeted therapy available for OSCC. Here, we reviewed the current findings from genomic analyses of OSCC and discuss how these studies inform on the biological mechanisms underlying OSCC. Exome sequencing revealed that the significantly mutated genes are mainly tumour suppressors. Mutations in FAT1, CASP8, CDKN2A, and NOTCH1 are more frequently found in OSCC when compared to non-OSCC head and neck cancers and other squamous cell carcinomas, and HRAS and PIK3CA are the only significantly mutated oncogenes. The distribution of these mutations also differs in populations with distinct risk habits. Gene expression-based molecular classification showed that OSCC can be divided into distinct subtypes and these have a preferential response to different types of therapies, suggesting that these classifications could have clinical implications. More recently, with the approval of checkpoint inhibitors for the treatment of cancers including OSCC, genomics studies also dissected the genetic signatures of the immune compartment to delineate immune-active and -exhausted subtypes that could inform on the immune status of OSCC patients and guide the development of novel therapies to improve response to immunotherapy. Taken together, genomics studies are informing on the biology of both the epithelial and stromal compartments underlying OSCC development, and we discuss the opportunities and challenges in using these to derive clinical benefit for OSCC patients.
Oral cancer secretome: identification of cancer-associated proteins

Chang HY, Hor SY, Lim KP, Zain RB, Cheong SC, Rahman MA, et al.

Electrophoresis, 2013 Aug;34(15):2199-208.
PMID: 23712713 DOI: 10.1002/elps.201300126

This study aims to identify cancer-associated proteins in the secretome of oral cancer cell lines. We have successfully established four primary cell cultures of normal cells with a limited lifespan without human telomerase reverse transcriptase (hTERT) immortalization. The secretome of these primary cell cultures were compared with that of oral cancer cell lines using 2DE. Thirty five protein spots were found to have changed in abundance. Unambiguous identification of these proteins was achieved by MALDI TOF/TOF. In silico analysis predicted that 24 of these proteins were secreted via classical or nonclassical mechanisms. The mRNA expression of six genes was found to correlate with the corresponding protein abundance. Ingenuity Pathway Analysis (IPA) core analysis revealed that the identified proteins were relevant in, and related to, cancer development with likely involvements in tumor growth, metastasis, hyperproliferation, tumorigenesis, neoplasia, hyperplasia, and cell transformation. In conclusion, we have demonstrated that a comparative study of the secretome of cancer versus normal cell lines can be used to identify cancer-associated proteins.
HPV infection and the alterations of the pRB pathway in oral carcinogenesis

Lim KP, Hamid S, Lau SH, Teo SH, Cheong SC

Oncol Rep, 2007 Jun;17(6):1321-6.
PMID: 17487385 DOI: 10.3892/or.17.6.1321

Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16(INK4A) and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16(INK4A) exon 1alpha. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (<10%). Strikingly, HPV was found to be present in all of our samples, suggesting that HPV plays a significant role in driving oral carcinogenesis. Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.
Alterations of the p14ARF-p53-MDM2 pathway in oral squamous cell carcinoma: MDM2 overexpression is a common event

Lim KP, Sharifah H, Lau SH, Teo SH, Cheong SC

Oncol Rep, 2005 Oct;14(4):963-8.
PMID: 16142358 DOI: 10.3892/or.14.4.963

The majority of global incidences of oral cancer occur in Asia, and the aetiology of oral cancer is different in Asia as it is in the West. However, whereas there is a growing understanding of the molecular mechanisms of oral cancer progression in the West, there is little progress in this understanding in Asia. In particular, the role of the p53 pathway in modulating cancer progression in Asian oral cancer remains unclear. In this study, we micro-dissected and analysed 20 well-differentiated oral squamous cell carcinoma specimens for alterations in the p53 pathway. We found that 6/20 samples contained mutations in the p53 gene which occurred in three hotspots, at codon 203, 218 and 296. Furthermore, 6/20 samples had a homozygous deletion of p14ARF, but notably p14ARF deletion and p53 mutation events were often independent and mutually exclusive. Strikingly, MDM2 was upregulated in 20/20 samples, but not in 3/3 normal tissue specimens. Taken together, these data suggest that inactivation of the p53 pathway is a frequent event in oral squamous cell carcinoma, which occurs by an aberration in one of a number of players in the p53 pathway.
Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer

Cirillo N, Hassona Y, Celentano A, Lim KP, Manchella S, Parkinson EK, et al.

Carcinogenesis, 2017 01;38(1):76-85.
PMID: 27803052 DOI: 10.1093/carcin/bgw113

The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16INK4A and with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16INK4A and minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion.
HER2/neu-Based Peptide Vaccination-Pulsed with B-Cell Epitope Induced Efficient Prophylactic and Therapeutic Antitumor Activities in TUBO Breast Cancer Mice Model

Nordin ML, Mohamad Norpi AS, Ng PY, Yusoff K, Abu N, Lim KP, et al.

Cancers (Basel), 2021 Oct 01;13(19).
PMID: 34638441 DOI: 10.3390/cancers13194958

Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2-P4) was further conjugated to a carrier protein (KLH), forming a KLH-GP2-P4 conjugate. The immunogenicity of KLH-GP2-P4 was compared with KLH-GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH-GP2-P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH-GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer.
Fulltext The influence of cultural and religious orientations on social support and its potential impact on medication adherence

Hatah E, Lim KP, Ali AM, Mohamed Shah N, Islahudin F

Patient Prefer Adherence, 2015;9:589-96.
PMID: 25960641 DOI: 10.2147/PPA.S79477

PURPOSE: Social support can positively influence patients' health outcomes through a number of mechanisms, such as increases in patients' adherence to medication. Although there have been studies on the influence of social support on medication adherence, these studies were conducted in Western settings, not in Asian settings where cultural and religious orientations may be different. The objective of this study was to assess the effects of cultural orientation and religiosity on social support and its relation to patients' medication adherence.
METHODS: This was a cross-sectional study of patients with chronic diseases in two tertiary hospitals in Selangor, Malaysia. Patients who agreed to participate in the study were asked to answer questions in the following areas: 1) perceived group and higher authority cultural orientations; 2) religiosity: organizational and non-organizational religious activities, and intrinsic religiosity; 3) perceived social support; and 4) self-reported medication adherence. Patients' medication adherence was modeled using multiple logistic regressions, and only variables with a P-value of <0.25 were included in the analysis.
RESULTS: A total of 300 patients completed the questionnaire, with the exception of 40 participants who did not complete the cultural orientation question. The mean age of the patients was 57.6±13.5. Group cultural orientation, organizational religious activity, non-organizational religious activity, and intrinsic religiosity demonstrated significant associations with patients' perceived social support (r=0.181, P=0.003; r=0.230, P<0.001; r=0.135, P=0.019; and r=0.156, P=0.007, respectively). In the medication adherence model, only age, duration of treatment, organizational religious activity, and disease type (human immunodeficiency virus) were found to significantly influence patients' adherence to medications (adjusted odds ratio [OR] 1.05, P=0.002; OR 0.99, P=0.025; OR 1.19, P=0.038; and OR 9.08, P<0.05, respectively).
CONCLUSION: When examining religious practice and cultural orientation, social support was not found to have significant influence on patients' medication adherence. Only age, duration of treatment, organizational religious activity, and disease type (human immunodeficiency virus) had significant influence on patients' adherence.
Fulltext Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

Lim KP, Chun NA, Gan CP, Teo SH, Rahman ZA, Abraham MT, et al.

Hum Vaccin Immunother, 2014;10(11):3214-23.
PMID: 25483651 DOI: 10.4161/hv.29226

The ever-increasing number of tumor-associated antigens has provided a major stimulus for the development of therapeutic peptides vaccines. Tumor-associated peptides can induce high immune response rates and have been developed as vaccines for several types of solid tumors, and many are at various stages of clinical testing. MAGED4B, a melanoma antigen, is overexpressed in oral squamous cell carcinoma (OSCC) and this expression promotes proliferation and cell migration. In this study, we have identified 9 short peptides derived from MAGED4B protein that are restricted in binding to the HLA subtypes common in the Asian population (HLA-A2, A11, and A24). The peptides had good binding affinity with the MHC-Class I molecules and stimulated ex-vivo IFN-gamma and Granzyme-B production in blood samples from OSCC patients, suggesting that they are immunogenic. Further, T cells stimulated with peptide-pulsed dendritic cells showed enhanced T-cell cytotoxic activity against MAGED4B-overexpressing OSCC cell lines. In summary, we have identified MAGED4B peptides that induce anti-tumor immune responses advocating that they could be further developed as vaccine candidates for the treatment of OSCC.
Fulltext CD4+CD25hiCD127low regulatory T cells are increased in oral squamous cell carcinoma patients

Lim KP, Chun NA, Ismail SM, Abraham MT, Yusoff MN, Zain RB, et al.

PLoS One, 2014;9(8):e103975.
PMID: 25153698 DOI: 10.1371/journal.pone.0103975

Regulatory T cells (Tregs), a subset of CD4+ T cells plays a pivotal role in regulating the immune system. An increase in Treg numbers enables cancer progression by dampening the immune system and allowing tumor cells to evade immune detection and destruction. An increase in Treg numbers and expression of inhibitory cytokines including TGF-β and IL-10 are mechanisms by which Tregs exert their immune suppressive function. However, the presence of Tregs and inhibitory cytokines in oral cancer patients is still unclear. In this study, the presence of circulating Tregs in 39 oral cancer patients and 24 healthy donors was examined by studying the presence of the CD4+CD25hiCD127low cell population in their peripheral blood mononuclear cells using flow cytometry. Serum levels of TGF-β and IL-10 were measured by ELISA. T cell subsets of OSCC patients were found to differ significantly from healthy donors where a decrease in CD8+ cytotoxic T cells and an increase in Tregs (CD4+CD25hiCD127low) were observed. Further, the ratio of CD8+ T cells/Tregs was also decreased in patients compared to healthy donors. The presence of Tregs was accompanied by a decrease in IL-10 but not TGF-β secretion in OSCC patients when compared to donors; in addition, the analysis also revealed that an increased presence of Tregs was accompanied by better patient survival. Amongst OSCC patients, smokers had significantly higher levels of TGF-β. It is apparent that the immune system is compromised in OSCC patients and the characterization of the Treg subpopulation could form a basis for improving our understanding of the perturbations in the immune system that occur during OSCC tumorigenesis.
Fulltext Identification of Four-Jointed Box 1 (FJX1)-Specific Peptides for Immunotherapy of Nasopharyngeal Carcinoma

Chai SJ, Yap YY, Foo YC, Yap LF, Ponniah S, Teo SH, et al.

PLoS One, 2015;10(11):e0130464.
PMID: 26536470 DOI: 10.1371/journal.pone.0130464

Nasopharyngeal carcinoma (NPC) is highly prevalent in South East Asia and China. The poor outcome is due to late presentation, recurrence, distant metastasis and limited therapeutic options. For improved treatment outcome, immunotherapeutic approaches focusing on dendritic and autologous cytotoxic T-cell based therapies have been developed, but cost and infrastructure remain barriers for implementing these in low-resource settings. As our prior observations had found that four-jointed box 1 (FJX1), a tumor antigen, is overexpressed in NPCs, we investigated if short 9-20 amino acid sequence specific peptides matching to FJX1 requiring only intramuscular immunization to train host immune systems would be a better treatment option for this disease. Thus, we designed 8 FJX1-specific peptides and implemented an assay system to first, assess the binding of these peptides to HLA-A2 molecules on T2 cells. After, ELISPOT assays were used to determine the peptides immunogenicity and ability to induce potential cytotoxicity activity towards cancer cells. Also, T-cell proliferation assay was used to evaluate the potential of MHC class II peptides to stimulate the expansion of isolated T-cells. Our results demonstrate that these peptides are immunogenic and peptide stimulated T-cells were able to induce peptide-specific cytolytic activity specifically against FJX1-expressing cancer cells. In addition, we demonstrated that the MHC class II peptides were capable of inducing T-cell proliferation. Our results suggest that these peptides are capable of inducing specific cytotoxic cytokines secretion against FJX1-expressing cancer cells and serve as a potential vaccine-based therapy for NPC patients.

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